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SATURDAY, July 21, 2012 (MedPage Today) — Two drugs — Qsymia (phentermine/topiramate) and Belviq (lorcaserin) — will soon be added to the armamentarium available for fighting obesity, but how, when, and "if" these new agents will be used is far from clear.

Qsymia may provide the bigger bang in terms of total weight loss, but it also requires an FDA risk evaluation and mitigation strategy (REMS), which means more paperwork for physicians.

Belviq, which targets a specific serotonin receptor, may be a safer option, but weight loss was less dramatic in clinical trials, according to physicians interviewed by MedPage Today.

"I don't see this as a horse race between the two drugs," Louis Aronne, MD, of Columbia University, who has treated patients with both drugs in clinical trials, told MedPage Today. "There will be specific situations where one or the other may be indicated."

When prescribing for an older diabetic patient, for instance, a clinician may want to use Belviq for its safety, Aronne said.

"Initially, physicians may not want to use phentermine" because of its association with the failed diet drug Fen-Phen, which was pulled from the market for heart valve risks, though the side effect was tied to its fenfluramine half. "But I think as time goes on, that won't be an issue," Aronne said.

The FDA required more postmarketing studies for Qsymia (a total of 10, compared with six for Belviq) and those studies focus on cardiovascular outcomes including stroke and MI for both.

The combination drug also carries more contraindications, with glaucoma and hyperthyroidism on the list of conditions that render patients ineligible. Those with recent or unstable heart disease are also excluded because of the drug's potential to increase heart rate.

Neither drug can be used in pregnant women, but only the combination agent has a specific risk attached to it. Topiramate, a treatment for seizures and migraine, has been shown to up the risk of oral cleft in newborns. For this, FDA has recommended monthly pregnancy tests for women on the drug, another potential barrier to use, industry analysts say.

Aronne said topiramate also carriers a higher risk of cognitive side effects such as memory or attention disturbances, but the FDA only warned about these effects with Belviq.

One advantage for Qsymia, though, is its once-daily dosing; Belviq patients will have to pop two pills a day. And Qsymia will make it to market first — possibly by the end of this year — since Belviq has been flagged by the DEA as a potential drug of abuse and will be subject to DEA scheduling, delaying its market entrance until the beginning of next year, according to analysts.

Mitigating Heart Risks

Both drugs affect the central nervous system, targeting behavioral pathways in order to make patients stick to dietary and exercise changes that must be coprescribed with the agents.

Belviq achieves that primarily by acting on serotonin pathways. It's a newly developed compound that activates the serotonin 2C receptor – unlike fenfluramine, which was foiled by its activation of the serotonin 2B receptor.

Patients with heart failure may have more of the 2B receptors in their heart tissue, according to the FDA, and the overstimulation may have caused valve problems. That shouldn't occur with compounds working on 2C, experts say.

For the combination agent, phentermine is a known appetite suppressant and is currently prescribed for weight loss, but only for a short period of time – about 3 to 6 weeks.

Aronne noted that it's given in a much lower dose in the combination drug, which should also be reassuring to clinicians.

"Some will say they don't want to prescribe it until the studies show that there's no cardiovascular risk," he said. "But the dose [of phentermine] is so low" that heart effects are less likely. (The recommended dose of the drug contains 7.5 mg phentermine and 46 mg topiramate.)

But Harlan Krumholz, MD, a cardiologist at Yale University, said he does have concerns about the new medications, given that efficacy studies are rarely large enough to turn up suspicious events.

"We need to have surveillance systems in place to get an early warning if these interventions turn out to cause a net harm," Krumholz said in an email to MedPage Today. Since obese patients likely have a higher prevalence of heart disease, he added, surveillance studies need to demonstrate whether these patients are having more events than would be expected.

A Long Dry Spell

Both mechanisms are vastly different than the only other FDA-approved drug for long-term weight loss, orlistat (Xenical), which prevents the absorption of fats from the diet. The drug also has an over-the-counter formulation (Alli), and both were slapped with an FDA warning about increased risk of liver injury in 2010.

Orlistat was the last contestant standing in the obesity market after FDA pulled sibutramine (Meridia) in 2010 over concerns about an increased risk of heart attack and stoke.

In 2007, drugmaker Sanofi withdrew its new drug application for rimonabant (Zimulti) after associated reports of depression and suicide. Ten years earlier, FDA pulled Fen-Phen as well as dexfenfluramine (Redux), which was also associated with heart valve problems.

Given a 13-year drought in new obesity drugs — a drought that tracked the nation's burgeoning obesity problem — this is an attractive market for pharmaceutical companies.

And three companies have been in the race for the brass ring: Arena Pharmaceuticals, Vivus, and Orexigen. Arena, maker of Belviq, and Vivus, the company that markets Qsymia, have completed the FDA approval hurdles, but Orexigen remains in the race.

Orexigen's entry is a drug called Contrave, a combination of bupropion and naltrexone, which was turned down by the FDA on its first pass at approval, as were Qsymia and Belviq.

But unlike the case with Belviq and Qsymia, when the FDA rejected Orexigen's initial application it told the drugmaker to conduct its cardiovascular outcomes study before resubmitting its new drug application.

McDavid Stilwell, a vice president at Orexigen, told MedPage Today that the company expects to complete enrollment in the cardiovascular study during the first quarter of 2013, with a target of 7,000 patients needed to hit a 1.5 percent event rate.

He said that Orexigen expects interim data from the study by the second half of 2013 and may resubmit its application next year. If all goes well, he said approval could come as early as the first quarter of 2014.

Hunger for New Drugs?

Most analysts say that the bigger question remains whether there will be much demand at all for the new obesity drugs given the market's less-than-stellar record.

"A number of treatments have made it to the market only to be withdrawn," James Coutcher, of Global Data Healthcare, told MedPage Today. "We expect physicians will be wary of prescribing either one."

Sales of Xenical have been sliding over the past 5 years, Coutcher noted, though this could have something to do with patient preference for its over-the-counter formulation, Alli.

Both phentermine and topiramate are available generically, so clinicians could prescribe these agents individually, Aronne said, though most will likely feel more comfortable writing for an approved agent that's easier to take.

More likely is that some clinicians may try combinations of the drugs, Aronne said: Belviq with phentermine, for instance.

Other clinicians doubt their colleagues will be that interested in working with the new agents. Lee Green, MD, MPH, a family medicine professor at the University of Michigan in Ann Arbor, wasn't enthusiastic about either option: "They really just don't work that well."

Even if they did offer 10 percent weight loss – unlikely, given that trials often represent idealized situations and real-world effects tend to be less amazing, Green said – many patients would still have a long way to go.

"That takes an obese 250-pound man with a BMI of 38 down to 34 — still obese, still at risk for diabetes, heart attacks, still having knee and back problems from the weight," Green said in an email.

"I understand the desire for a miracle pill, a silver bullet, to deal with the very difficult and stubborn problem of obesity, but I don't think it's going to be that easy," he added. "I will be surprised if either one is still on the market in 5 years."

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